title: Detection of hypoxia by [18F]EF5 in atherosclerotic plaques in mice.
abstract: OBJECTIVE
  Atherosclerotic plaques with large lipid cores and inflammation contain regions of hypoxia. We examined the uptake of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide ([18F]EF5), a specific marker of hypoxia labeled for positron emission tomography, in mouse atherosclerotic plaques.
  
  
  RESULTS
  Atherosclerotic mice of 2 different genetic backgrounds (low-density lipoprotein receptor-/- apolipoprotein B100/100 and insulin-like growth factor II/low-density lipoprotein receptor-/- apolipoprotein B100/100) were first fed a Western diet to induce development of plaques with variable phenotypes and then injected with [18F]EF5. C57BL/6N mice served as controls. Aortas were dissected for biodistribution studies, autoradiography, histology, and immunohistochemistry. Uptake of [18F]EF5 was significantly higher in the aortas of mice with large atherosclerotic plaques than in the C57BL/6N controls. Furthermore, autoradiography demonstrated, on average, 2.0-fold higher [18F]EF5 uptake in atherosclerotic plaques than in the adjacent normal vessel wall. Hypoxia in plaques was verified by using an EF5 adduct-specific antibody and pimonidazole. The blood clearance of [18F]EF5 was slow, with blood radioactivity remaining relatively high up to 180 minutes after injection.
  
  
  CONCLUSIONS
  Large atherosclerotic plaques in mice contained hypoxic areas and showed uptake of [18F]EF5. Despite its slow blood clearance, the high uptake of [18F]EF5 in plaques suggested that plaque hypoxia is a potential target for identifying high-risk plaques noninvasively.
authors.affiliation: Turku PET Centre, Department of Medicine, Turku University Hospital, and Institute of Forensic Medicine and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 4-8, PO Box 52, FI-20520 Turku, Finland. johanna.silvola@utu.fi
authors.forename: Johanna M U
authors.initials: JM
authors.lastname: Silvola
authors.forename: Antti
authors.initials: A
authors.lastname: Saraste
authors.forename: Sarita
authors.initials: S
authors.lastname: Forsback
authors.forename: V Jukka O
authors.initials: VJ
authors.lastname: Laine
authors.forename: Pekka
authors.initials: P
authors.lastname: Saukko
authors.forename: Suvi E
authors.initials: SE
authors.lastname: Heinonen
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Anne
authors.initials: A
authors.lastname: Roivainen
authors.forename: Juhani
authors.initials: J
authors.lastname: Knuuti
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D053299:Apolipoprotein B-100 / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001345:Autoradiography; D004195:Disease Models, Animal; D017341:Etanidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005838:Genotype; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics; D000860:Hypoxia / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009593:Nitroimidazoles; D010641:Phenotype; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014018:Tissue Distribution; D005466:Fluorocarbons
chemical_list: D053299:Apolipoprotein B-100; D017341:Etanidazole; D005462:Fluorine Radioisotopes; D006845:Hydrocarbons, Fluorinated; D007335:Insulin-Like Growth Factor II; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; D011973:Receptors, LDL; C513121:IGF2 protein, mouse; C096011:2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide; D005466:Fluorocarbons; C033815:pimonidazole